The current outbreak of pandemic influenza (H1N1) 2009 demonstrates
yet again how enigmatic, unpredictable and challenging the influenza
virus is. First isolated in 1933 by Laidlaw, Andrewes and Smith (1) and
one of the first human viruses to be isolated, it has been intensively
studied in the minutest of details over many decades. Yet in 2009 this
remarkable virus still baffles virologists and perplexes epidemiologists
with its unpredictability and its penchant for upsetting prevailing
dogmas. (2)

For almost a decade, the global community had been anticipating
that the avian influenza A (H5N1) virus would be responsible for the
next pandemic, which should be imminent if the 15-50-year cycle of
pandemics were to hold. This would also fit in with influenza A (H5N1)
being a new subtype of virus to humans, as was the case with previous
pandemics--H1N1 in 1918, H2N2 in 1957 and H3N2 in 1968. Today, 40 years
after the last pandemic, it is the novel swine influenza virus that has
launched the current pandemic even though it is not a new subtype--H1N1
subtype has circulated in humans since 1977. It is, however, certainly a
virus novel to humans, antigenically and biologically quite distinct
from human H1N1. Where has this virus come from, and what does it hold
for the world and for South Africa in particular?

Classic swine influenza virus of the H1N1 subtype was identified as
far back as 1931 as a cause of respiratory disease in pigs. (1) The
virus is endemic in pig herds in North and South America, parts of
Europe, East Asia and Africa (Kenya). Human infections with this virus
have been an occupational risk resulting in sporadic cases of an
influenza-like illness but with little or no human-to-human
transmission. In 1976, however, an outbreak of swine flu in a military
camp (Fort Dix, New Jersey) was responsible for 230 cases and severe
illness in some 13 soldiers with 1 death. (3) Here there was clear
human-to-human transmission, but the infection mysteriously died out.
More recently a derivative of the classic swine influenza virus was
detected. Pigs are susceptible and are frequently infected by influenza
viruses from birds and humans. It is therefore not too surprising that a
novel swine influenza virus arose as a result of the exchange of genetic
material, referred to as reassortment, from influenza viruses from
swine, avian and human sources. (4) This triple reassortant swine
influenza A (H1N1) virus was first detected in human patients in
December 2005 in the USA and, until the present novel influenza A (H1N1)
outbreak in April 2009, 11 cases of infection had been reported, in 10
of which there had been contact with pigs. While the clinical
presentation resembles human influenza illness in many respects, some
important differences have been described. The disease was mainly found
in children and young adults (median age 10 years), the incubation
period was somewhat longer than human influenza (median 3.5 days), and
unusual clinical signs were described in about a quarter of the
patients, who presented with gastro-intestinal symptoms of vomiting and
diarrhoea.

The current pandemic influenza (H1N1) 2009 virus arose from a
subsequent reassortment event from the triple reassortant swine
influenza A (H1N1) virus. (5) The latter virus contains 5 genes from the
classic swine virus (haemagglutinin HA, nucleoprotein NP, neuraminidase
NA, matrix M, and nonstructural NS), 2 genes from avian influenza virus
(polymerase PB2 and PA) and a single gene from human influenza virus
(polymerase PB1). In the case of pandemic influenza (H1N1) virus, the NA
and M swine genes, which were of North American origin, were replaced by
genes of Eurasian origin. The effect has been to create a novel
reassortant virus able to transmit efficiently from human to human and
spreading within a matter of 6 weeks throughout the world. Early in June
the WHO declared a global pandemic. The virus is now well established in
the human population--the 100 000 mark having been passed in mid-July,
although the true tally is greatly in excess of this. Fortunately the
disease has been relatively mild in the majority of cases--no more
serious than the regular annual seasonal influenza. What is different is
the greater involvement of younger individuals (median of 10-20 years of
age and relative sparing of older persons), a pattern quite unlike
seasonal influenza and more akin to past pandemics. Risk factors for
severe disease include those conventionally described for seasonal
influenza (with the exception of the elderly) but now also including
obesity and pregnancy.

Well over 100 laboratory-confirmed cases have been detected in
South Africa as at mid-July and therefore, as has been internationally
recommended, routine testing of all suspect cases as well as daily
number counting has been stopped as this would add very little value in
managing the outbreak, which has undoubtedly spread well beyond the
numbers confirmed through laboratory testing. The winter season could
well promote significant spread of the virus, as it does for seasonal
influenza, further aggravated by the crowded and inadequately ventilated
living conditions of a large proportion of our population. Underlying
immunosuppressive diseases such as HIV and TB are clearly also
aggravating factors--again focusing on the young adult population. The
effect of immunosuppression on viral excretion and the epidemiological
consequences will also need to be investigated. Influenza is an
infection of very high transmissibility and very little can be done to
prevent the virus spreading through a non-immune population. It is hoped
that an effective vaccine will become available for widespread use by
the end of the year. For the individual, personal hygiene practices such
as cough and sneeze etiquette, frequent hand washing and social
distancing will reduce the chances of transmission.

Given the notorious unpredictability of influenza virus, the
long-term future of the pandemic cannot be forecast. (2) Unlike previous
pandemics, pandemic influenza (H1N1) 2009, although not a new subtype of
influenza virus, does represent a virus that is new to the human
population both antigenically and biologically. The extent of
cross-protection from prior exposure to human H1N1 influenza, either
from past natural infection or from vaccination, still needs to be
defined although the relative sparing of older individuals probably does
represent some degree of cross-protection.

At present, oseltamivir remains the drug of choice for both
treatment and post-exposure prophylaxis in high-risk persons, although
the clinical efficacy for pandemic influenza (H1N1) has not yet been
adequately established. (5) The virus remains sensitive to both
oseltamivir and zanamivir; however, the explosion of resistance to
oseltamivir by H1N1 human influenza virus over the past 2 years has
taken virologists aback--in South Africa all 2008 H1N1 isolates tested
highly resistant to the drug. (6)

Barry D Schoub

Executive Director

National Institute for Communicable Diseases/National Health
Laboratory Service Johannesburg